Antibiotics are low-molecular weight antimicrobial agents that are produced as secondary metabolites by microorganisms that inhabit soil. For instance, Penicillium and Cephalosporium produce beta-lactam antibiotics (e.g., penicillin, cephalosporin, and their relatives). Actinomycetes (e.g., the Streptomyces species) produce tetracyclines, aminoglycosides (e.g., streptomycin and its analogs), macrolides (e.g., erythromycin and its analogs), chloramphenicol, ivermectin, rifamycins, and most other clinically-useful antibiotics that are not beta-lactams. Bacillus species (e.g., B. polymyxa and Bacillus subtilis) produce polypeptide antibiotics (e.g. polymyxin and bacitracin), while B. cereus produces zwittermicin.
The modern era of antibiotic therapy began with Fleming's 1929 discovery of penicillin, and Domagk's 1935 discovery of synthetic sulfonamides. Spurred by the need for antibacterial drugs during World War II, penicillin was isolated, purified and injected into experimental animals. The substance was found to not only cure infections, but also to possess low toxicity. This finding marked the beginning of the era of antibiotic use in human drug therapy and the intense search for similar antimicrobial agents of low toxicity that could be used to treat infectious diseases. The rapid isolation of streptomycin, chloramphenicol and tetracycline followed, and these and several other antibiotics were in clinical usage by the 1950's.
Antibiotics are used therapeutically to treat bacterial infections. Several types of antibiotics, classified according to their mechanism of action, are currently employed. The known types of antibiotics include, e.g., cell wall synthesis inhibitors, cell membrane inhibitors, protein synthesis inhibitors, and inhibitors that bind to or affect the synthesis of DNA or RNA.
Cell wall synthesis inhibitors, such as beta lactam antibiotics, generally inhibit some step in the synthesis of bacterial peptidoglycan. Penicillin is generally effective against non-resistant streptococcus, gonococcus and staphylococcus. Amoxycillin and Ampicillin have broadened spectra against Gram-negative bacterias. Cephalosporins are generally used as penicillin substitutes, against Gram-negative bacteria, and in surgical prophylaxis. Monobactams are generally useful for the treatment of allergic individuals.
Cell membrane inhibitors disorganize the structure or inhibit the function of bacterial membranes. Polymyxin, produced by Bacillus polymyxis, is a cell membrane inhibitor that is effective mainly against Gram-negative bacteria and is usually limited to topical usage.
Protein synthesis inhibitors include the tetracyclines, chloramphenicol, the macrolides (e.g. erythromycin) and the aminoglycosides (e.g. streptomycin). Aminoglycosides have been used against a wide variety of bacterial infections caused by Gram-positive and Gram-negative bacteria. Aminoglycosides bind to the bacterial RNA in manifestation of their activity. Davis, B. D. Microbiol. Rev. 1987, 51, 341-350. Mingeot-Leclercq, M.-P.; Glupczynski, Y.; Tulkens, P. M. Antimicrob. Agents Chemother. 1999, 43, 727-737. Moazed, D.; Noller, H. F. Nature 1987, 327, 389-394. Shaw, K. J., Rather, P. N.; Hare, R. S.; Miller, G. H. Microbiol. Rev. 1993, 57, 138-163. Streptomycin has been used extensively as a primary drug in the treatment of tuberculosis. Gentamicin is active against many strains of Gram-positive and Gram-negative bacteria, including some strains of Pseudomonas aeruginosa. Kanamycin is active at low concentrations against many Gram-positive bacteria, including penicillin-resistant staphylococci.
The structures of two aminoglycoside antibiotics, paromomycin and gentamicin C1a, bound to the template sequences of ribosomal RNA (rRNA), have been determined recently by NMR. Fourmy, D.; Recht, M. I.; Blanchard, S. C.; Puglisi, J. D. Science 1996, 274, 1367-1371; (a) Fourmy, D.; Recht, M. I.; Puglisi J. D. J. Mol. Biol. 1998, 277, 347-362; (b) Fourmy, D.; Yoshizawa, S.; Puglisi, J. D. J. Mol. Biol. 1998, 277, 333-345; (c) Recht, M. I.; Fourmy, D.; Blanchard, S. C.; Dahlquist, K. D.; Puglisi, J. D. J. Mol. Biol. 1996, 262, 421-436; (d) Yoshizawa, S.; Fourmy, D.; Puglisi, J. D. EMBO J. 1998, 17, 6437-6448. These and other studies show that the neamine-class of aminoglycosides bind specifically to the A-site region on the 16S subunit of rRNA. Hence, neamine serves as a minimal structural motif for such binding. Fourmy, D.; Recht, M. I.; Blanchard, S. C.; Puglisi, J. D. Science 1996, 274, 1367-1371; Kotra, L. P.; Haddad, J.; Mobashery, S. Antimicrob. Agents Chemother. 2000 (in press)). As such, aminoglycosides are a suitable class of compounds that could be effective antibiotics.
Neamine itself is a poor antibiotic and is not clinically useful. However, clinically useful aminoglycosides include, e.g., gentamicin, amikacin and neomycin. These compounds, however, face the possibility of clinical obsolescence because of the function of aminoglycoside-modifying enzymes, such as what already happened with kanamycins. (Wright, G. D.; Berghuis, A. M.; Mobashery, S. Aminoglycoside antibiotics: Structures, functions and resistance; Rosen, B. P., Mobashery, S., Eds.; Plenum Press: New York, 1998; pp. 27-69.
The tetracyclines are protein synthesis inhibitors that consist of eight related antibiotics which are all natural products of Streptomyces, although some can now be produced semisynthetically. Tetracycline, chlortetracycline and doxycycline are the best known. The tetracyclines are broad-spectrum antibiotics with a wide range of activity against both Gram-positive and Gram-negative bacteria. Tetracyclines have some important uses, such as in the treatment of Lyme disease.
Chloramphenicol is a protein synthesis inhibitor that has a broad spectrum of activity but it exerts a bacteriostatic effect. It is effective against intracellular parasites such as the rickettsiae. It is infrequently used in human medicine except in life-threatening situations (e.g. typhoid fever). Macrolide antibiotics, such as erythromycin, are protein synthesis inhibitors that are active against most Gram-positive bacteria.
Some antibiotics affect the synthesis of DNA or RNA, or can bind to DNA or RNA so that their messages cannot be read. For example, nalidixic acid is a synthetic quinoloid antibiotic which is active mainly against Gram-negative bacteria. The main use of nalidixic acid is in treatment of lower urinary tract infections (UTI). In addition, the rifamycins has greater bactericidal effect against the bacteria that causes tuberculosis than other anti-tuberculosis drugs and is also useful for treatment of tuberculosis meningitis and meningitis caused by Neisseria meningitidis. 
Growth factor analogs are structurally similar to bacterial growth factors, but do not fulfill their metabolic functions in cells. For example, sulfonamides have been extremely useful in the treatment of uncomplicated UTI caused by E. coli, and in the treatment of meningococcal meningitis.
The worldwide exploitation of antibiotics to treat infectious diseases has grown dramatically over the last forty years. In 1954, two million pounds of antibiotics were produced in the United States. Today, the figure exceeds 50 million pounds. According to the Centers Disease Control (CDC), humans consume 235 million doses of antibiotics annually.
Widespread misuse or overuse of antibiotics has fostered the spread of antibiotic resistance and has contributed to the development of a serious public health problem. Antibiotic resistance occurs when bacteria that cause infection are not killed by the antibiotics taken to stop the infection. The bacteria survive and continue to multiply, causing more harm. For example, the bacterium Staphylococcus aureus is a major cause of hospital acquired infections that, historically, responded satisfactorily to the antibiotic vancomycin. Recently, however, many strains of S. aureus have been found to be resistant to vancomycin. Moreover, the death rate for some communicable diseases such as tuberculosis have started to rise again, in part because of increases in bacterial resistance to antibiotics.
The development of new drugs is an essential component to strategies designed to reverse the problem of bacterial resistance, particularly in treating infectious diseases (e.g., bacterial infections). Accordingly, there is a need to identify additional compounds to treat infectious diseases (e.g., bacterial infections). The compounds can preferably be administered orally.